2-nitroimidazoles

ABSTRACT

2-NITROIMIDAZOLES SUBSTITUTED IN THE 1-POSITION WITH A LOWER ALKYL AMIDE OR A LOWER ALKYL AMINE WHICH ARE USEFUL AS GERMICIDES AND ANTI-PROTOZOAL AGENTS.

United States Patent 3,646,057 Z-NITROIMIDAZOLES Alden Gamaliel Beaman,North Caldwell, N.J., and William Paul Tautz, New York, N.Y., assignorsto Hotimann-La Roche Inc., Nutley, N .J. No Drawing. Filed Apr. 16,1969, Ser. No. 816,838 Int. Cl. C07d 49/36 US. Cl. 260-309 12 Claims-ABSTRACT OF THE DISCLOSURE Z-nitroimidazoles substituted in thel-position with a lower alkyl amide or a lower alkyl amine which areuseful as germicides and anti-protozoal agents.

SUMMARY OF THE INVENTION In accordance with this invention, it has beenfound that Z-nitroimidazoles selected from the group consisting ofcompounds of the formula:

B3 (II) wherein n is an integer from 2 to 6; R is hydrogen or loweralkyl; R is lower alkyl, halo lower alkyl, aryl, aryl lower alkyl,aryloxy lower alkyl, or a substituted or unsubstituted or 6 memberedheterocycic aromatic ring; R and R are hydrogen, lower alkyl, and takentogether with the attached nitrogen form a 5 or 6 membered substitutedor unsubstituted heterocyclic ring; and acid addition salts thereof areactive against bacteria, pathogenic yeasts and protozoa.

In accordance with this invention, the compounds of Formula I above areformed by reacting an alkali metal salt of '2-nitroimidazole with acompound of the formula:

reacting an alkali metal salt of Z-nitroimidazole with a compound of theformula:

R2 X(CHg)nN R3 wherein X, n, R and R are as above.

DETAILED DESCRIPTION OF THE INVENTION The term halogen as usedthroughout the specification includes all forms of halogens, i.e.,chlorine, fluorine, bromine and iodine, with bromine, chlorine andfluorine being preferred. The term lower alkyl as used throughout thespecification denotes both branched chain and straight chain saturatedhydrocarbons containing from 1 to 7 carbon atoms such as methyl, ethyl,n-propyl, iso propyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl andthe like. The term lower alkoxy as used throughout the specificationdesignates lower alkoxy radicals having from 1 to 7 carbon atoms such asmethoxy, ethoxy, isopropoxy, etc. The term halo-lower alkyl as usedthroughout the specification denotes mono halo lower alkyl as well as:poly halo lower alkyl radicals such as trichloromethyl,trifluoromethyl, 1,2 dichloroethyl, and the like.

The term aryl includes monocuclear aryl groups such as phenyl orsubstituted phenyl. The aryl substituents can be a polynuclear arylgroup such as naphthyl, anthryl, phenanthryl, azulyl, or substitutedpolynuclear aryl groups. In accordance with a preferred embodiment ofthis invention, the term aryl designates phenyl or substituted phenyl.Furthermore, the preferred substituted aryl radicals are those arylradicals wherein one or more (preferably from 1 to 2) hydrogen groupshas been replaced by halogen, lower alkyl, lower alkoxy,tn'fluoromethyl, nitro or amino.

The term aryl lower alkyl designates aryl lower alkyl groups whereinaryl and lower alkyl are defined as above. The term aryloxy lower alkyldesignates an aryloxy lower alkyl moiety wherein aryl and lower alkylare defined as above. Among the aryloxy groups are included phenoxy,chlorophenoxy, anthryloxy, etc. The term 5 or 6 membered heterocyclicgroups includes both substituted and unsubstituted heterocyclic groupscontaining from 1 to 2 hetero atoms which can be either oxygen, nitrogenor sulfur.

When R in the compound of Formula I is a dior tri-substituted halo loweralkyl, the preferred alkyl group is methyl. Among the preferred dihaloor trihalo substituents on the methyl group which constitutes apreferred embodiment of R in the compound of Formula I above aretrifiuoromethyl, trichloromethyl, dichloromethyl, etc.

When R is aryloxy lower alkyl, the preferred compound of Formula I abovehas the formula:

CH N

wherein R and n are as above, and R and R are each independentlyhydrogen, halogen, lower alkyl, nitro, amino, lower alkoxy ortrifiuoromethyl, and a is an integer from 1 to 6. In a preferredembodiment of compounds of the Formula I-A, R is hydfogen and n is aninteger of from 2 to 4. Among the preferred phenoxy substituents in thecompound of Formula I-A are included phenoxy, pchlorophenoxy,o-chlorophenoxy, o,p-dichlorophenoxy, p-methylphenoxy, p-ethylphenoxy,o-methoxyphenoxy, 0- nitrophenoxy, p-aminophenoxy,p-trifiuoromethylphenoxy, etc.

When R in compounds of the Formula I is aryl or aryl lower alkyl, thepreferred form of the compound of Formula I has the formula:

wherein R, R R and n are as above, and m is an integer of from 0 to 6.In a preferred embodiment of compounds of the Formula I-B, R ishydrogen, and m is an integer from 0 to 4. Among the preferred phenylsubstituents in the compound of Formula I-B are included phenyl,pchlorophenyl, o-chlorophenyl, o,p-dichlorophenyl, p-methylphenyl,p-ethylphenyl, o-methoxyphenyl, o-nitrophenyl, p-aminophenyl,p-trifluoromethylphenyl, etc. a

When R in compounds of the Formula I is a sub stituted or unsubstitutedheterocyclic aromatic ring moiety,

the preferred form of the compound of Formula I has the formula:

wherein R, R R and n are as above, and B is a 5 or 6 membered aromaticheterocyclic ring moiety containing from 1 to 2 hetero atoms selectedfrom the group consisting of nitrogen, oxygen or sulfur. In accordancewith a preferred embodiment of Formula IC, R is hydrogen and n is aninteger from 2 to 4. Among the preferred heterocyclic moieties which canconstitute B are included, pyridyl, e.g., 3-pyridyl and S-pyridyl,furanyl, thiofuranyl, pyrrolyl, imidazolyl, thienyl, pyrimidyl, e.g.,5-pyrimidyl, pyrazinyl and the like.

When R and R in the compound of Formula II form a 5 or 6 memberedheterocyclic, a preferred form of the compound of Formula H has theformula:

I KN (CHQn-N N V (II-A) wherein n is as above, and Z represents loweralkylenc, loweralkylene-azalower alkylene,N-loweralkyl-lowerallqllene-azaloweralkylene,loweralkylene-oxaloweralkylene or loweralkylene-thialoweralkylene so asto form with the nitrogen atom to which they are attached a 5 or 6membered nitrogen heterocycle. Hence, Z includes such radicals aspentamethylene, tetramethylene, ethyleneoxyethylene andethyleneazaethylene, which can be substituted or unsubstituted. Amongthe preferred heterocyclic moieties formed by N and Z are included,N-lower alkyl piperazinyl, pyrrolidinyl, p-iperazinyl, morpholinyl andpiperidinyl.

The compound of Formulae I and II as well as their acid addition saltswith pharmaceutically acceptable acids are useful as anti-microbialagents. They are particularly useful against bacteria such as Klebsiellapneumoniae, Salmonella schottmuelleri, Salmonella: typhy, Staphylococcusaureus, Streptococcus hemolyticus and the like. They are alsoparticularly useful in combatting protozoa such as Trichomonasvaginalis, T richomonas foetus, Histomonas meleagradis, Endamoeba lzistolytz'ca, Trypanosomes, e.g., T. cruzi, T. rhodesiense, T. congolense,and the like. Therefore, the compounds of this invention can be used asgermicides, and anti-protozoal agents, e.g. trichomonacides,histomonacides, trypanacides Compounds of Formulae I and II areparticularly well suited for the treatment of protozoal infections,e.g., trichomoniasis and histomoniasis.

For use in the treatment of infectious diseases such as Trichomoiasis.Trypanosomiasis, Histomoniasis, etc., the compounds of this inventioncan be administered orally parenterally or topically. They can beformulated into conventional pharmaceutical dosage forms in admixturewith organic or inorganic inert carrier materials which are suitable forenteral, parenteral or topical application such as, for example, water,gelatin, lactose, starch, magnesium stearate, talc, vegetable oil, gumarabic, polyalkylene glycols, Vaseline, etc., or other conventionalexcipients. They can be prepared in the form of tablets, dragees,suppositories, capsules, ointments, creams, etc., or in liquid form suchas solutions, suspensions, emulsions and the like. They can containother additives such as preserving, stabilizing, wetting or emulsifyingagents, salts for varying the osmotic pressure, buffers and the like orthey can be formulated with other therapeutically useful materials.Typical oral dosages of the novel compounds of this invention and theirsalts range from about 30 to about mg./kg. animal body weight thoughhigher or lower dosages adjusted to species and individual requirementsmay also be used.

The fact that the compounds of Formulae I and II above are effective incombatting trichomoniasis can be seen from various in vivo tests in-miceusing standard testing procedures. For instance, amides such as N-[2-(2- nitro l-imidazolyl)ethyl]propionamide, N-[2-(Z-nitro-limidazolyl)ethyljtrifiuoroacetamide, N [3(Z-nitro-limidazolyl)propyljtrifluoroacetamide hydrate have been foundto be active in vivo against Trichomonas vaginalis in mice at dosages offrom 26 mg./kg. p.o. to 60 mg./kg. p.o., and higher, whereas all ofthese compounds have LD s of greater than 500 mg./ kg. p.o. in mice.Another example of the effectiveness of the compounds of F ormulae I andII can be seen by the fact that compounds such as 4[2-(2nitro-l-imidazolyl)ethyl]morpholine, N-{Z-(Z- nitrol-imidazolyl)ethyl]propionamide, N'-[3-(2-nitro-limidazolyl)propyl1trifiuoroacetamide hydrate, and N-[Z-,(2-nitro-l-imidazolyl)ethylJbenzamide have been found to be active invivo in mice against Trichomonas foetus at dosages of from 4 mg./kg.p.o. to 50 mg./kg. p.o. and higher while these compounds have LD s inmice of greater than 500 mg. p.o.

The effectiveness of the amines of Formula II can be seen by the factthat compounds such as 1-(2-aminoethyl)- 2 nitro-imidazole and1[2-(2-nitro-l-irnidazolyl)ethyl]- 4-methylpiperazine, have been foundto be active in vivo against Trichomonas vagirzalis in mice at dosagesof from 30 to 75 mg./kg. p.o., while these compounds have LD s in miceof greater than 500 rug/kg. p.o.

Acid addition salts of the novel compounds of this invention i.e., thecompounds of Formulae I and II above, are prepared by reacting withinorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, etc., or with organic acids such as oxalic acid, acetic acid,lactic acid, tartaric acid and the like. Non-pharmaceutically acceptableacid addition salts can be converted into pharmaceutically acceptableacid addition salts by neutralization followed by reaction with asuitable pharmaceutically acceptable acid. 7

The compound of Formula III above is formed by reacting the hydrohalidesalt of a compound of the formula:

wherein X, R and n are as above, with an acid halide of the formula:

X CR (VI) wherein X is a halogen and R is as above. The compound ofFormula V is reacted with the compound of Formula VI to produce thecompound of the Formula- III above in the presence of an inorganicalkali metal base. Generally, this reaction is carried out in an aqueousmedium. In carrying out this reaction, any conventional alkali metalbase such as sodium hydroxide or potassium hydroxide can be utilized.Furthermore, in carrying out this reaction, it is preferred to utilizeat least 2 moles of the base per mole of the hydrohalide salt of FormulaV above. Generally, from about 2 to 5 moles of the base are utilized permole of the compound of Formula V above. This reaction is carried out atreduced temperatures, i.e., temperatures of from about -20 'C. to 0? C.However, this reaction can take place at any temperature of from about40 C. to about 20 C.

The reaction of a 2-nitroi-midazole with a compound of Formula III or acompound of Formula IV is preferably carried out by employing an alkalimetal salt of 2-nitroirnidazole. The alkali metal salt ofZ-nitroimidazole can be conveniently prepared by dissolving the2-nitroimidazole. starting material in an alkali metal lower alkoxide,e.g., sodium methoxide, potassium methoxide, etc. The

reaction of the alkali metal salt of the 2-nitroimidazole with thecompound of the Formula III above or IV is suitably carried out in thepresence of an inert organic solvent. Any conventional inert organicsolvent can be utilized. Among the preferred inert organic solvents areincluded, N,N-dimethyl-formamide, N,N-1dimethyl-acetamide,dimethyl-sulfoxide, lower alkanols, e.g., methanol, ethanol, etc.,hydrocarbon solvents such as toluene, etc. Alternatively, where one ofthe reactants is a liquid, the reaction can be carried out in theabsence of any solvent. This reaction is suitably carried out at anelevated temperature, preferably in the range of about 90 C. to about160 C.

When R is lower alkyl or hydrogen and R is hydrogen in the compound ofFormula H above, the compound of Formula II above has the followingformula:

l II CNO2 9 (CH9) 11 x11 (II-B) wherein R and n are as above.

The compound of Formula II-B can be converted in accordance with anembodiment of this invention into the compound of Formula I above byreacting the compound of Formula 11-3 with an acid of the formula:

wherein R is as above, in the presence of a dehydrating agent. Anyconventional dehydrating agent can be utilized in carrying out thisreaction. Among the conventional dehydrating agents, the dilower alkylor dicyclo alkyl carbodiimides wherein the cycloalkyl group containsfrom 3 to 7 carbon atoms such as dicyclohexyl carbodiimide arepreferred. This reaction can be carried out in an organic solvent underanhydrous conditions. Any conventional inert organic solvent such as thesolvents hereinbefore mentioned, can be utilized in carrying out thisreaction. Generally, this reaction is carried out at reducedtemperatures, i.e., temperatures from about 20 C. to 0 C. However, anytemperature of from about 40 C. to about 40 C. can be utilized incarrying out this reaction.

In accordance with another embodiment of this invention, the compound ofthe Formula II-B wherein n is 2 and R is hydrogen can be prepared byreacting 2-nitroimidazole with ethyleneimine. This reaction is carriedout in excess ethyleneimine. In this reaction excess ethyleneimine actsas the solvent medium. This reaction is simply carried out by mixing theethyleneimine and the 2-nitroimidazole. Since this reaction isexothermic in nature, the mixing step is best carried out at lowtemperatures, i.e., from about -20 C. to about 0 C. However, anytemperature from about 40 C. to about 10 C. can be utilized in carryingout the mixing step. Once the ethyleneimine and the 2-nitroimidazole aremixed, cooling is stopped and thetemperature of the reaction medium israised to the reflux temperature by means of the heat generated by thereaction. If the temperature of the reaction is raised to a very highlevel by reason of the heat generated by the reaction medium, thetemperature of the can be modified byexternal cooling.

This invention will be more fully understood from the following exampleswhich are intended to illustrate the invention and are not to beconstrued to be limitative thereof. All temperatures are stated indegrees centigrade. Where a vacuum is utilized the pressure is stated inmm. Hg.

EXAMPLE 1 Preparation of N-[2-(2-nitro-1-imidazolyl)ethyl] acetamide Asolution of 70.5 g. (1.76 moles) of sodium hydroxide in 400 ml. of waterwas cooled to 15 and 90.0 g. (0.775 mole) of 2-chloroethylaminehydrochloride was added and the solution was cooled to 18 and 50 ml.(den. 1.10. 55.3 g., 0.705 mole) of acetyl chloride was added dropwisewith stirring over a period of 22 minutes maintaining the temperature at18 to 5. The mixture was stirred in the cold for an additional 15minutes, the pH was adjusted to 6 with 19 ml. of glacial acetic acid,the solution was saturated with sodium chloride and extracted with 2times 1 liter of chloroform. The chloroform extracts were combined,dried over anhydrous magnesium sulfate, filtered and the chloroformremoved in vacuo to leave N-(2-chloroethyl)acetamide as a yellow oil.

A solution of 10.0 g. (88.4 mmoles) of sublimed 2- nitroimidazole, ml.of dimethylformamide and 19.2 ml. of 4.56 N solution of sodium methoxidein methanol was made yellow by the addition of a pinch of 2-nitr0-imidazole and was heated to 152 and then cooled to With stirring 13.06g. (11.0 ml., den. 1.19, 107 mmoles) of N-(Z-chloroethyl)acetamide wasadded and the mixture was stirred at 120-130 for one hour. The mixturewas cooled and filtered. The solid was slurried in 15 ml. of water andfiltered. There remained insoluble crude product, M.P. 164.5166.5. Thedimethylformamide filtrate was evaporated in vacuo (0.3 mm., bath 52) togive the solid which was slurried in 25 ml. of absolute ethanol,filtered, washed with 2 times 10 m1. of ethanol and dried. This plus theproduct from the salt was ground thoroughly with a mixture of 60 ml. ofsaturated aqueous sodium carbonate solution plus 75 ml. of water,filtered and Washed with 25 ml. of water and dried. Evaporation of theaqueous sodium carbonate solution to about 45 ml. in a shallow dish gaveadditional product. The combined crude product was recrystallized from185 ml. of boiling absolute ethanol to give pale yellow crystals ofN-[2-(2-nitro-1-imidazolyl)ethyl] acetamide, M.P. 165- 166.

Airig =315 mp 6:7800.

EXAMPLE 2 Preparation of N-[2-(2-nitro-1-imidazolyl)ethyl] benzamide Asolution of 41.6 g. (1.04 moles) of sodium hydroxide in 250 ml. of waterwas cooled to 15 and 55.5 g. (0.478 mole) of 2-chloroethylaminehydrochloride was added and the solution cooled to incipient freezingand 50 ml. (den 1.22, 61.0 g., 0.435 mole) of benzoyl chloride was addeddropwise over a period of 27 min. The mixture Was stirred in the coldfor 5 minutes, the pH was adjusted to 6 with 9 ml. of glacial aceticacid, and the solid was filtered and washed with 6 times 10 ml. ofwater. The filter cake was sucked dry and dissolved in ml. boilingethanol. The solution was cooled in the freezer to give N- 2-chloroethylbenzamide.

A stirred solution of 10.3 g. of sublimed 2-nitroimidazole in 19.4 ml.(88.5 mmoles) of 4.56 N solution of sodium methoxide in methanol plus100 ml. of dimethylformamide was made yellow by the addition of a smallamount of 2-nitroimidazole and was heated to 152, cooled to 118 and 19.5g. (106 mmoles) of N-(2-chloroethyl)benzamide was added. The mixture wasstirred at reflux (154) for 30 minutes, cooled to 10, the sodiumchloride filtered and the dimethylformamide removed in vacuo (0.4 mm.,bath 50) to give a brown solid. This was ground with 30 ml. of absoluteethanol, filtered, washed with 2 times 7.5 ml. of ethanol and dried. Itwas shaken with a mixture of 600 ml. of ethyl acetate plus 40 ml. ofsaturated aqueous sodium carbonate solution plus ml. of water. The ethylacetate layer was washed with 2 times 20 ml. of water, dried overanhydrous magnesium sulfate, filtered and the filtrate evaporated togive crystalline solid. This was recrystallized from 100 ml. of boilingabsolute ethanol (Norit A) to give needles of N- [2(2nitro-1-imidazolyl)ethyl]benzamide, MP. 1405-- 141.5.

x232 314 In EXAMPLE 3 Preparation of N- [2-(2-nitrol-irnidazolyl)ethyl]phenyl acetamide To a solution of 36.6 g. (0.904 mole) of sodiumhydroxide in 225 ml. of water at was added 48.0 g. (0.413 mole) of2-chloroethylamine hydrochloride and the whole was cooled to and withstirring 50 ml. (den. 1.16, 58.0 g., 0.376 mole) of phenylacetylchloride was added dropwise over a period of 11 minutes maintaining thetemperature in the range of 20 to 10. The mixture was stirred in thecold for 30 minutes, the pH adjusted to 6 with 10 ml. of glacial aceticacid and the solid was filtered, Washed with 4 times 20 ml. of water,sucked dry and dissolved in 100 ml. of boiling ethanol. The solution wascooled in the freezer to give N-(2-chloroethyl)phenylacetamide.

A solution of 10.3 g. of sublimed Z-nitroimidazole in 100 ml. ofdimethylformamide plus 19.4 ml. (8-8.5 mmoles) of 4.65 N solution ofsodium methoxide in methanol was made yellow by the addition of a smallamount of 2-nitroimidazole, heated to 153 and cooled to 130. Withstirring 21.9 g. (110.4 moles) of N-(2-chloroethyl) phenylacetamide wasadded and the mixture stirred at 129-139 for 40 minutes and then cooledto 10. The sodium chloride was filtered and the dimethylformamide wasremoved in vacuo (0.3 mm., bath 60) to give a tan solid plus oil whichwas shaken while warm with 30 ml. of absolute ethanol, cooled andfiltered and the solid washed with 2 times 10 ml. of ethanol and dried.This was shaken with 800 ml. of ethyl acetate plus 50 ml. of saturatedaqueous sodium carbonate solution plus 12 ml. of water, the layersseparated and the ethyl acetate washed with 2 times 30 ml. of water,dried over anhydrous magnesium sulfate, filtered and the filtrate letevaporate to give crystalline solid. This was recrystallized from 125ml. of boiling absolute ethanol (Norit A) to give N-[2-(Z-nitro-l-imidazolyl)ethyl]phenylacetamide as crystals, M.P. 125.5-127.

amon 31 m A solution of 55.2 g. (1.38 moles) of sodium hydrox- 4 ide in300 m1. of water was cooled to 5 and 73.7 g. (0.633 mole) of2-chloroethylarnine hydrochloride was added and the solution cooled to18 and ml. (den. 1.06, 53.2 g., 0.575 mole) of propionyl chloride wasadded dropwise with stirring over a period of 17 minutes maintaining thetemperature at -18 to l2. The mixture was stirred in the cold for anadditional 18 minutes, g. of sodium chloride was added and the pH wasadjusted to 6 with 15 ml. of glacial acetic acid. The solid presentmelted just above 0 and was extracted out with 2 times 500 ml. ofchloroform. The chloroform extracts were combined, dried over anhydrousmagnesium sulfate, filtered and the chloroform removed in vacuo to give69 g. of N-(2-chloroethyl)propionamide as a light yellow oil.

A solution of 12.5 g. of sublimed 2-nitroimidazole in ml.dimethylformamide plus 23.5 ml. (107 mmoles) of 4.56 N solution ofsodium methoxide in methanol was made light yellow by the addition of asmall amount of 2-nitroimidazole and was heated to 153 and let cool to122. Then 18.4 g. (136 mmoles) of N-(Z-chloroethyl) propionamide wasadded and the mixture was stirred at 125-135 for 45 minutes, cooled to12, the sodium chloride filtered and the dimethylformamide removed invacuo (0.3 mm., bath 62) to give an oil which partially solidified. Thiswas slurried in 5 m1. of absolute ethanol, filtered and washed with 2times 2.5 ml. of ethanol and dried. This was shaken with a mixture of500 m1. of ethyl acetate plus 45 ml. of saturated aqueous sodiumcarbonate solution plus 10 ml. of distilled Water. The ethyl acetatelayer was washed with 2 times 15 ml. of water, dried over anhydrousmagnesium sulfate, filtered and the filtrate allowed to evaporate in ashallow dish to give crystals. These were dissolved in 30 ml. of boilingabsolute ethanol and the solution cooled in the freezer to give N-[2-(2-nitro-1-imidazolyl)ethyl]propionarnide as pale yellow crystals,M.P. 95.5-97.5

EXAMPLE 5 Preparation ofN-[Z-(Z-nitro-l-imidazolyl)ethyl]trifluoroacetamide A solution of 29.0g. (0.725 mole) of sodium hydroxide in 175 ml. of water was cooled to-18 and 39.0 g. (0.336 mole) of 2-chloroethylamine hydrochloride wasadded. The whole solution was cooled to 18 and with stirring 5 0 g.(0.375 mole) of trifluoroacetyl chloride was bubbled in over a period of17 minutes maintaining the temperature at -18 to 10. The pH at the endof the addition was 8. The mixture was stirred in the cold for 20minutes, the pH was adjusted to 7 with 6 ml. of glacial acetic acid andthe solid was filtered, washed with 3 times 20 ml. of cold water anddried to give N-(Z-chloroethyl) trifluoroacetamide.

A solution of 10.5 g. (93.0 mmoles) of 2-nitroimidazole in 100 ml. ofdimethylformamide plus 21.0 ml. of 4.56 N solution of sodium methoxidein methanol was heated to 152, cooled to and 18.5 g. (106 mmoles) ofN-(Z-chloroethyl)trifiuoroacetamide was added. The mixture was stirredat 129-134 for 1.5 hours, cooled, the sodium chloride filtered and thedimethylformamide removed in vacuo (0.3 mm., bath 56). The resultingsolid was slurried in 125 ml. of ethanol, cooled, filtered, washed with15 ml. of ethanol and dried. It was shaken with a mixture of 750 ml. ofethyl acetate plus 60 ml. of saturated aqueous sodium carbonate solutionplus 15 ml. of water. The ethyl acetate layer was extracted with 3 times15 ml .of water, dried over anhydrous magnesium sulfate, filtered andthe filtrate allowed to evaporate to give tan crystals which wererecrystallized from 125 ml. of boiling absolute ethanol to giveN-[2-(2-nitr0-l-imidazolyl)ethyl] trifiuoroacetamide as pale yellowfiakelet crystals, M.P. -146.

REE 313 my EXAMPLE 6 Preparation of N-[3-(2-nitro-1-imidazolyl)propyl]trifluoroacetamide hydrate A solution of 29.0 g. (0.725 mole) of sodiumhydroxide in ml. of water was cooled to -18 and 72.8 g. (0.332 mole) of3-bromo-propylamine hydrobromide was added and cooled to 17, and withstirring 49 g. (0.37 mole) of trifluoroacetyl fluoride was bubbled inovera period of 24 minutes maintaining the temperature in the range of12 to 8. The pH at the end was 9. The mixture was stirred in the coldfor an additional 20 minutes and the pH was adjusted to 6 with 8 ml. ofglacial acetic acid. The solid was filtered, washed with 3 times 15 ml.of cold water and dried to give N-(3-bromopropyl) trifiuoroacetamide.

An orange solution of 10.3 g. of sublimed Z-nitroimidazole in 100 ml. ofdimethylformamide plus 19.65 mi.

(89.5 mmoles) of 4.56 N solution of sodium methoxide in methanol wasmade light yellow by the addition of a small amount of 2-nitroimidazole.The solution was heated to 152, cooled to 135 and 23.6 g. (102 mmoles)of N-(3-bromopropyl)trifiuoroacetamide was added and the mixture wasstirred at 125-130 for 35 minutes. The dimethylformamide was removed invacuo (0.2 mm., bath 60) and the pasty residue was stirred with 100 ml.of chloroform, the sodium bromide filtered and the filtrate evaporatedin vacuo to give an amber oil. This was shaken with 200 ml. of ethylacetate plus 20 ml. of saturated aqueous sodium carbonate solution plus5 ml. of water. The ethyl acetate layer was washed with 7.5 ml. ofwater, dried over anhydrous magnesium sulfate, filtered and the filtrateallowed to evaporate in a shallow dish. The oil which formed wasslurried in 25 ml. of absolute ethanol, and the solution allowed toevaporate slowly to give crystals. After several hours these wereslurried in 5 ml. of absolute ethanol, filtered, washed with 3 ml. ofethanol and dried. The ethanol filtrate plus wash was allowed toevaporate to give more crystals which were slurried in 5 ml. ofchloroform, filtered, washed with 3 ml. of chloroform and dried. Theywere recrystallized from ml. of ethanol to giveN-[3-(2-nitro-1-imidazolyl)propyl]-trifiuoroacetamide hydrate ascrystals, M.P. 57-59.

Preparation of N-[3-(2-nitro-1-imidazolyl) propyl1acetamide A solutionof 32 g. (0.8 mole) of sodium hydroxide in 200 ml. of water was cooledtol8 and 80.0 g. (0.365 mole) of 3-bromopropylamine hydrobromide wasadded and the whole was cooled to 16 and 24.5 ml. (den. 1.10, 27.0 g.,0.344 mole) of acetyl chloride was added dropwise with stirring over aperiod of 10 minutes maintaining the temperature between 16 and 0. Themixture was stirred in the cold for 20 minutes, the pH was adjusted to 6with 7 ml. of glacial acetic acid and the murky mixture was extractedwith 2 times 500 ml. of chloroform. The chloroform extracts werecombined, dried over anhydrous magnesium sulfate, filtered and thechloroform removed in vacuo. The resulting oily N-(3-bromopropyl)acetamide crystallized on standing at room temperature.

An orange solution of 10.3 g. of sublimed Z-nitroimidazole in 100 ml. ofdimethylformamide plus 19.6 ml. (89.5 mmoles) of 4.56 N solution ofsodium methoxide in methanol was made light yellow by the addition of asmall amount of Z-nitroimidazole. The solution was heated to 152, cooledto 120 and 20.0 g. (111 mmoles) of N-(3-bromopropyl)acetamide was addedand the mixture stirred at 125-133 for 45 minutes. The dimethylformamidewas removed in vacuo and the resulting oil was shaken with 125 ml. ofchloroform, the sodium bromide was filtered and the filtrate wasconcentrated in vacuo to an amber oil. This was shaken with a mixture of450 ml. of ethyl acetate plus 40 ml. of saturated aqueous sodiumcarbonate solution plus 6 ml. of water. The ethyl acetate layer waswashed with 8 ml. of water and was then dried over anhydrous magnesiumsulfate, filtered and allowed to evaporate in a shallow dish to give ayellow, moist crystalline solid. This was sucked dry on a small Biichnerfunnel, washed with 2 ml. of absolute ethanol and dried. It wasrecrystallized from 45 ml. of hot water to giveN-[3-(2-nitro-1-imidazolyl)propyl]acetamide as crystals, M.P. 65.5-67".

e=7300. A sample was recrystallized twice again from water, M.P.67.5-68.5".

10 EXAMPLE 8 Preparation of B-(Z-nitro-l-imidazolyl) ethyl diethylamineTo a stirred slurry of 5.00 g. (44.2 mmoles) of powdered and sievedsublimed 2-nitroimidazole and 8.35 g. (48.6 mmoles) of B-chloroethyldiethylamine hydrochloride in 50 ml. of dimethylformamide was added 21.0ml. of 4.44 N solution of sodium methoxide in methanol. Sodium chlorideprecipitated and the slurry became pink. A pinch of azomycin was addedand the slurry became yellow. The sodium chloride was filtered and tothe filtrate was added 1.05 g. sodium iodide and the mixture was stirredand heated at 103119 for 30 minutes, cooled, the salt removed byfiltration and the filtrate evaporated to an amber oil in vacuo (oilpump). On cooling, the oil partially solidified and the slush was shakenwith 75 ml. of carbon tetrachloride and filtered. The filtrate wasevaporated to give a moist solid which was dissolved in 20 ml. ofbenzene at room temperature and -20 ml. of hexane was added and thesolution was warmed to -35 and about 1 g. of Norit A was added andfiltered. The filtrate was warmed slightly and hexane was added untilthe solution just became hazy and then a few drops of benzene was addedto give a clear solution. This solution was cooled in the freezer togive B-(Z- nitro-l-imidazolyl)-ethyldiethylamine as yellow fiakelets,M.P. 54-55 EES? 314 u EXAMPLE 9 Preparation of4-[2-(2-nitro-1-imidazolyl)ethyl] morpholine To a stirred mixture of10.0 g. (88.4 mmoles) of sublimed 2-nitroimidazole, 17.4 g. (93.5mmoles) of N-(B- chloroethyl)morpho1ine hydrochloride and ml. ofdimethylformamide was added very slowly 39.5 ml. of 4.56 N solution ofsodium methoxide in methanol. The sodium chloride was filtered, 1.0 g.sodium iodide was added and the solution was stirred at 107-1 19 for 30minutes. The mixture was cooled to 15 the sodium chloride filtered andthe dimethylformamide removed in vacuo (0.3 mm., bath 45). The residuewas shaken with a mixture of 350 m1. of ethyl acetate plus 60 ml. ofsaturated aqueous sodium carbonate solution plus 30 ml. of water. Thelayers were separated and the ethyl acetate was extracted first with 25ml. of saturated aqueous sodium carbonate solution plus 15 ml. of waterand finally with 35 ml. of water. The ethyl acetate solution was allowedto evaporate to give crystals which were recrystallized from 40 ml. ofWarm absolute ethanol to give4-[2-(2-nitro-1-imidazo1yl)ethyl]morpholine as lath shaped crystals,M.P. 5658.

Milli 31 3 u EXAMPLE 10 Preparation of N-[2-(2-nitro-1-imidazolyl)ethyl] piperidine To a stirred mixture of 10.0 g. (88.4 mmoles) ofsublimed 2-nitroimidazole, 18.0 g, (97.5 mmoles) of N-(B-chloroethyl)piperidine hydrochloride and 100 ml. of dimethylformamidewas added very slowly 42.0 ml. of 4.56 N solution of sodium methoxide inmethanol. The sodium chloride was filtered, 1.0 g. sodium iodide wasadded and the solution was stirred at 118 for 50 minutes. The mixturewas cooled, the sodium chloride was filtered and the dimethylformamideremoved in vacuo (0.2 mm., bath 52) to give an amber oil. This wasdissolved in absolute ethanol and the ethanol let evaporate and thisprocess repeated until the oil became crystalline. The crystals wereslurried in 8 ml. of absolute ethanol, filtered, and washed with 2 times6 ml. of absolute ethanol to give product, M.P. 63.5-66". This wasrecrystallized from 50 ml. of boiling absolute ethanol (Norit A) to giveN-[2-(2-nitro-1-imidazolyl)ethylJpiperidine as light yellow rods, M.P.66-68".

EXAMPLE 11 Preparation of N-[2-(2-nitro-l-irnidazolyDethyl]-2-nitro-5-furoamide To a cold solution of 1.6 g. (7.7 mmoles) ofdicyclohexylcarbodiimide in 100 ml. of dry ethyl acetate was added amixture of 1.06 g. (6.5 mmoles) of 2-nitro-5- turoic acid and 1.05 g.(6.5 mmoles) of 1-(2-aminoethyl)-2-nitroimidazole (described herein)with stirring. The mixture was stirred in an ice bath for 1 hour and wasthen stirred at room temperature overnight. The solid which formed wasfiltered, washed with ethyl acetate, acid dried, wt. 2 g. This wasstirred with 200 ml. of absolute ethanol at room temperature which dissolved 1.4 g. of dicyclohexylurea. The remaining 0.7 g. of solid wasrecrystallized from 125 ml. of boiling absolute ethanol to giveN-[2-(2-nitro-l-imidazolyl)ethyl]- 2-nitro-5-furoamide M.P. 173175. Theethyl acetate filtrate from the 2.1 g. of solid was extracted andsaturated NaCl solution. The ethyl acetate layer was filtered, thefiltrate was evaporated to dryness, and the resulting solid wasrecrystallized from 125 ml. of boiling absolute ethanol to giveadditional N-[Z-(nitro-l-imidazolyl) ethyl]-2-nitro-5-furoamide, M.P.172.5-173.5

EXAMPLE 12 Preparation of N-[2- (Z-nitro-l-imidazolyl) ethyl]- anisamideA solution of 17.6 g. of NaOH in 160 ml. of water was cooled below and23.2 g. of 2-cl1loroethylamine hydrochloride was added. Acetone (200ml.) was cooled to 20 and 34.1 g. of anisoylchloride was added. To thisstirred solution at 19 the aqueous solution of NaOH+ClCH CH NH was addedslowly over a period of 5 minutes, the maximum temperature being Theslurry was stirred at 0 to 10 for 25 minutes and 120 ml. of water wasadded. The slurry was cooled to -8, :filtered, and the solid was washedwith water and sucked as dry as possible. The slightly moist solid wasrecrystallized from 125 :ml. of boiling absolute ethanol to give 24.0 g.of N-(2-chloroethyl)anisamide M.P. l25.5-127.

A mixture of 10.0 g. of sublimed 2-nitroimidazole plus 100 ml. ofdimethylformarnide (D.M.F.) was stirred and 19.6 ml. of 4.56 N sodiummethoxide in methanol was added. The mixture was heated to 152, cooledto 125, and 21.8 g. of N-(2-chloroethyl)anisamide was added. The mixturewas heated with stirring at 120-130 for 40 minutes. The D.M.F. wasremoved in vacuo and the residue was shaken with a mixture of 2 l. ofethylacetate plus 50 ml. of saturated aqueous Na CO solution plus 100m1. of water, filtered, and the layers separated. 'Ihe Preparation ofN-[2-(Z-nitro-l-imidazolyl)ethyl]- p-chlorophenoxy-acetamide A mixtureof 37.4 g. of p-chlorophenoxyacetic acid and 56 g. of thionylchloridewas refluxed for one hour and the excess thionyl chloride was removed.in vacuo. The crude p-chlorophenoxy-acetyl chloride was dissolved in 200ml. of acetone, the solution cooled to 20, and then with stirring a coldsolution prepared from 170 ml. of water, 191.6 g. of NaOH, and 23.2 g.of 2-chloroethylamino hydrochloride was added slowly over a period of 6minutes maintaining the temperature below 10. To the resulting clearsolution was added about 125 ml. of water whereupon a crystalline solidformed. The slurry was cooled to 6, filtered, washed with water, stirredwith 200 ml. of 1 N NaOH solution for 10 minutes, refiltered, washedthoroughly with water, dried, and recrystallized from 36 ml. of boilingabsolute ethanol to give N-(2- chloroethoxy) p chlorophenoxyacetamide,M.P. 94.5- 95.5

A mixture of 6.7 g. of Z-nitroimidazole plus ml. of dimethylformamide(D.M.F.) was stirred and 13.1 ml. of 4.56 N sodium methoxide in methanolwas added. The solution was heated to 152, cooled to 130 and 14.7 g. ofN-(Z-chloroethyl) p chlorophenoxyacetamide was added and the mixture washeated at 120-130 for 40 minutes. The D.M.F. was removed in vacuo andthe residue was shaken with a mixture of 250 ml. of ethyl acetate, 25ml. of water and 20 ml. of saturated aqueous sodium carbonate solution.The ethyl acetate layer wasrwashed with 25 ml. of saturated NaClsolution and the ethyl acetate was removed in vacuo to give a moistsolid which was slurried in 35 ml. of ethanol, filtered, washed withethanol, and dried. This solid was recrystall zed from 225 ml. ofboiling ethanol (charcoal) to give N-[2-(2-nitro- 1-imidazolyl)ethyl] pchlorophenoxy-acetamide" M.P. 137.7-138.7.

RKE 287 my E=5400 and 313 III L, E=79U0.

EXAMPLE 14 Preparation of N-[2-(Z-nitro-1-imidazolyl)ethyl]-2-nitro-5-furoarnide To a solution of 1.64 g. (41 mmoles) of NaOH in 10ml. of water there was added 2.2 g. (19 mmoles) of 2-chloroethylaminehydrochloride. The mixture was cooled to 10 and 2.91 g. (17 mmoles) ofZ-nitro- S-furoyl chloride was added in small portions with stirringover a period of 20 min. The mixture was stirred in the cold for severalhours and thetan solid which formed was filtered oil, washed and dried.It was recrystallized from hot ethanol to giveN-(Z-chloroethyl)-2-nitro-5- furoamide.

A solution of 0.52 g. (4.6 rnrnoles) of sublimed 2-nitroimidazole in 15ml. of dimethylformamide plus 1.0 ml. of 4.56 N sodium methoxide inmethanol was heated to 152, cooled to 100 and 2.0 g. (9.2 mrnoles) ofN-(2- chloroethyl)-2-nitro-5-furoamide was added. The mixture wasstirred at 120-150 for 1 hr. The dimethylformamide was removed in vacuo,and the residual solid was shaken with a mixture of 5 ml. of water, 5ml. of saturated aqueous Na CO solution and 100 ml. of ethylacetate. Thelayers were separated, and the ethylacetate was washed with 25 ml. ofwater, and evaporated. The re sulting solid was leached with 15 ml. ofethanol at room temperature and the insoluble material wasrecrystallized three times from ethanol to giveN-[2-(2-nitro-1-imidazolyl)ethyl]-2-nitro-5-furoamide as crystals, M.P.171 173.

EXAMPLE 15 I Preparation of 1-[2-(Z-nitro-l-imidazolyl)ethyl]-4-methylpiperazine A solution of 1.58 g. (14 mmoles) of sublimed2-nitroimidazole in 3.01 ml. of 4.56 N sodium methoxide in methanol plus25 ml. of dimethylformarnide was heated to 152, cooled to 105. 2.53 g.(15.6 moles) of 1-(2- chloroethyl)-4-methylpiperazine (J. C. Craig, R.J. Harrison, M. E. Tate, R. H. Thorp, and R. Ladd, Australian Journal ofChemistry, 9, 89-94 (1956)) was added and the mixture was heated at -105for 50 min. The solvent was removed in vacuo and the residual oil wasshaken with a mixture of 14 ml. of 1 N NaOH plus ml. of ethylacetate.The layers were separated, the aqueous layer extracted with ethylacetateand the combined organic layers extracted with 15 ml. of 1 N NaOH. Theorganic layer was dried over anhydrous Na CO and the ethyl acetate wasremoved in vacuo (100 mm.) to give an oil which was dissolved in 10 ml.of ether which upon cooling gave the product, having melting point61-63". Recrystallized from ml. of ether there was obtained1-[2-(2-nitrol-imidazolyl)ethyl] 4-methylpiperazine as crystals, M.P.62.5-64. EXAMPLE 16 Preparation of 1-(Z-aminoethyl)-2-nitroimidazoleSublimed Z-nitroimidazole (20.0 g., 177 mmoles) was dissolved in 200 ml.of ethyleneimine in a 1,000 ml. flask with three condensers whilecooling in an ice bath. The solution was then removed from the ice bathwhereupon the reaction mixture spontaneously heated to refluxtemperature and refluxed for 30 minutes. The excess ethyleneimine wasremoved in vacuo (finally 0.3 mm., bath 70) to give a viscous oil whichwas cooled and poured into 400 ml. of ice water. The resulting solutionwas extracted with seven times 500 ml. of chloroform. The combinedchloroform extracts were dried over anhydrous sodium sulfate andevaporated to an oil which crystallized. The crystals were slurried in25 ml. of ether, filtered and washed with ether. The crystals were thenrecrystallized from 110 ml. of ethyl acetate to give crystals M.P. 90.5-'92. A second crystallization gave 1-(2-aminoethyl)-2- nitroimidazoleM.P. 91-92.

EXAMPLE 17 Preparation of N-[2-(2-nitro1-imidazo1yl)ethyl]dichloroacetamide imidazolyl)ethyl1dichloroacetamide as crystals M.P.1l6.5-1l8.5.

. EXAMPLE 18 Preparation of N-methyl-N-[Z-(2-nitro-1-imidazoly1)ethyl]propionamide A solution of 28.8 g. of sodium hydroxide in 250 ml.of distilled water was cooled to 0 C. and 39.0 g. of methyl aminoethylchloride hydrochloride was added. The solution was cooled to l0 C. and32.2 g. of propionyl chloride was added dropwise with stirring at such arate that the temperature of the reaction mixture was to 0 C. Themixture was then cooled at 0 C. for 30 minutes, and was then extractedwith three 250 ml. portions of chloroform. The combined chloroformextracts were dried over MgSO filtered, the chloroform removed in vacuo,and the remaining oil distilled to give N methyl N (2chloroethyl)propionamide B.P.

A solution of 9.6 g. of sublimed Z-nitro-imidazole in 100 ml. ofN,N-dimethylformamide. plus 20.7 ml. of 4.1 N sodium methoxide inmethanol was heated to 152 C., cooled to 135 C. and 14.0 g. ofN-methyl-N-(2-chlo roethyl)propionamide was added. The mixture wasstirred at 120-130' C. for one hour. The dimethyl formamide was removedin vacuo to give an oil which soon crystallized. This solid was shakenin a separatory funnel with a mixture of 500 ml. of ethylacetate plus 25ml. saturated aqueous Na CO solution plus 25 ml. of water. The aqueouslayer was separated, and the organic layer was extracted with 'a mixtureof 25 ml. of saturated aqueous Na CO solution plus 25 ml. of water andthen 14 with 25 ml. of water. The ethylacetate layer was dried over NaSO filtered, and concentrated in vacuo to an oily solid. This was washedwith 25 ml. of ether to give crude product M.P. 77-78.5 C. This wasrecrystallized from 2 parts of boiling absolute ethanol to giveN-methyl- N [2 (2 nitro 1 imidazolyl)ethyl]propionamide, M.P. 77.5-79 C.

EXAMPLE 19 Preparation of N-[2-(2-nitro-l-imidazolyl)ethyl] butyramide Asolution of 19.2 g. of sodium hydroxide in 170 ml. of distilled waterwas cooled to 0 C. to 22.1 g. of 2- chloroethylamine hydrochloride wasadded. This solution was cooled to 10 C., and 23.4 g. of butyrylchloridewas added drop-wise with stirring at such a rate. that the reactiontemperature was 10 C. to 0 C. A solid formed. The mixture was thencooled at 0 C. for one hour, and was extracted with three 200 m1.portions of ethyl acetate. The combined extracts were dried over Na SOfiltered, and the filtrate evaporated in vacuo to give an oil which wasdistilled to give N-(2-chloroethyl) butyramide B.P. 83-83.5 C./ 0.05 to0.1 mm. which crystallized at room temperature.

A solution of 9.6 g. of sublimed 2-nitroimidazole in ml. ofN,N-dimethylformamide plus 20.7 ml. of 4.1 N sodilun methoxide inmethanol was heated to 152 C., cooled to 140 C. and 14.0 g. ofN-(2-chloroethyl)butyramide was added. The mixture was stirred at -130C. for 1.75 hours, and the dimethyl formamide was removed in vacuo. Theresidual oil plus solids was shaken in a separatory funnel with amixture of 300 ml. of ethylacetate plus 25 ml. of saturated aqueous NaCO solution plus 50 ml. of water. The aqueous layer was separated andthe organic layer was extracted with a mixture of 15 ml. of saturated NaCO solution plus 35 ml. of water and then with 25 ml. of water. Theethylacetate layer was dried over MgSO filtered, and the filtrate wasevaporated in vacuo to solids which were. washed with 30 ml. of etherand dried to give 10.2 g. of crude product M.P. ll9-121 C. This wasrecrystallized from 1 part of boiling absolute ethanol to giveN-[2-(2-nitro-l-imidazolyl) ethyl]butyramide M.P. l19.5l21.5 C

EXAMPLE 20 Preparation of N-[2-(Z-nitro-l-imidazolyl)ethyl]-isobutyramide To a solution of 19.2 g. of sodium hydroxide in 170 m1. ofdistilled water at 0 C. was added 22.1 g. of 2-chloroethylaminehydrochloride. This solution was cooled to l0 C. and 23.4 g. ofisobutyryl chloride was added dropwise with stirring at such a rate thatthe reaction temperature was maintained at 15 to l0 C. The mixture wasthen cooled at 0 for 30 minutes and extracted with three times 250 ml.of chloroform. The combined chloroform extracts were dried over MgSO-filtered, and the filtrate was evaporated in vacuo to an oil. This wasdistilled to give 19.4 g. of product B.P. 8l-83/0.05 to 0.1 mm. Thissolidified and was washed with 20 ml. of petroleum ether, filtered, anddried to give N-(Z-chloroethyl)isobutyramide M.P. 4548 C.

A solution of 6.6 g. of sublimed 2-nitroimidazole in 70 ml. ofN,N-dimethylformamide plus 14.2 ml. of 4.1 N sodium metholate inmethanol was heated to 152, cooled to 100, and 7.9 g. ofN-(2-chloroethyl)isobutyramide was added and the mixture was heated at120- C. for 1.5 hours. The dimethylformamide was removed in vacuo, andthe residual oil plus solids was shaken in a separatory funnel with amixture of 100 ml. of ethylacetate plus 15 ml. of saturated aqueous NaCO solution plus 15 ml. of water. The aqueous layer was separated, andthe organic layer was extracted with a mixture of 15 ml. of saturatedaqueous Na CO solution plus 15 ml. of water and then with 25 ml. ofwater.

15 The ethylacetate layer was dried over Na SO filtered, and thefiltrate was evaporated to dryness in vacuo to give 8.0 g. of crudeproduct. This was recrystallized from 10 ml. of boiling absolute ethanolto give N-[Z-(Z- nitro 1 imidazolyl)ethyl]-isobutyramide MP. 112.5- 114C.

EXAMPLE 21 Preparation of capsules containing fl-(2-nitro-limidazolyl)ethyl diethylamine Per capsule, mg.

,B-(Z-nitr'o-l-imidazolyl)ethyl diethylamine 50 Lactose, U.S.P. 125 Cornstarch, U.S.P. 30 Talc, U.S.P. 5

Total weight 210 Procedure 1) B (Z-nitro-1-imidazoly1)ethyl diethylaminewas mixed with lactose and corn starch in a suitable mixer.

(2) The mixture was further blended by passing through a Fitzpatrickcomminuting machine with a No. 1A screen with knives forward.

(3) The blended powder was returned to the mixer, the tale added andblended thoroughly.

(4) The mixture was filled into No. 4 hard shell gelatin capsules on acapsulating machine.

EXAMPLE 22 Preparation of tablets containing fi-(2-nitro-limidazolylethyl diethylamine Per tablet, mg.

[3-(Z-nitro-1-imidazolyl)ethyl diethylamine 25.00 Lactose, U.S.P. 64.50Corn starch 10.00

Magnesium stearate 0.50

Procedure Preparation of capsules containing N-[2-(2-nitro- 1-imidazolyl) ethyl] acetamide Per capsule, mg. N- 2-(2-nitro-1-imidazolylethyl] acetamide Lactose, U.S.P. 125

Corn starch, U.S.P. 30

Talc, U.S.P. 5

Total weight 210 Procedure 1) N [2-(2-nitro-l-imidazolyl)ethylJacetamidewas mixed with lactose and corn starch in a suitable mixer.

(2) The mixture was further blended by passing through a Fitzpatrickcomminuting machine with a No. 1A screen with knives forward.

(3) The blended powder was returned to the mixer, the talc added andblended thoroughly.

(4) The mixture was filled into No. 4 hard shell gelatin capsules on acapsulating machine.

16 EXAMPLE 24.

Per tabl N- 2- 2-nitro-1-imidazolyl) ethyl] acetamide 25.00

Lactose, U.S.P. 64.50

Corn starch 10.00

Magnesium stearate 0.50

Procedure (1) N [2-(Z-nitro-l-imidazolyl)ethyl]acetamideivas mixed withthe lactose, corn starch andrna'gnes iun r stearate in a suitable mixer.j,

(2) The mixture was further blended by pa ssing through a Fitzpatrickcomminuting machine fitted with a No. 1A screen with knives forward. k i"j (3) The mixed powders were slugged on a tablet cornpressing machine.I a

(4) The slugs were comminuted to a'suitable mesh size (No. 16 screen)and mixed well. j

(5) The tablets were compressed at a tablet weight of mg. using tabletpunches having a diameterof 'approximately A".

What is claimed is: s N

1. A compound selected from the groupfconsistingof compounds of theformula:

wherein n is an integer from 2' to 6; R is hydrogen or lower alkyl; R islower alkyl, halo-lower alkyl,

lower alkylene or wherein R and R are each independently selected fromthe group consisting of hydrogen, halogen, lower alkyl, lower alkoxy,nitro, amino or trifluoromethyl andpharmaceutically acceptable acidaddition salt thereof.

2. A compound of claim 1 wherein R is a lower alkyl. 3. A compound ofclaim 2 whereinfisaid compound is N-[2-(Z-nitro-l-imidazolyl) ethyl]acetamide.

4. A compound of claim 2 wherein said compoundvis N- [2-Z-nitrol-imidazolyl ethyl] propionamide.

5. A compound of claim 2 wherein said compound is N methyl N [2 (2 nitro1 -imidazolyl).ethyl] propionamide.

6. A compound of claim 2 wherein said compound is N-[-2-(2-nitro-1-imidazolyl)ethyl]-isobutyramide. v

7. A compound of claim 2 wherein said compound'isN-[3-(2-nitro-1-imidazolyl)propyl]acetarnide..

8. A compound of claim 1 :wherein R is a hal lower alkyl. 9. A compoundof claim 8 wherein said compound is N-[3 (2nitro-1-imidazoly1)propyl]trifiuoroacetamide hydrate. 3 10. A compoundof claim 1 wherein said compound is N- [2- (Z-nitro-l-imidazolyl) ethyl]phenylacetamide. 11. A compound in accordance with claim Lwherein saidcompound has the formula:

17 wherein R and n are as above, and R and R are inde pendentlyhydrogen, halogen, nitro, amino, lower alkyl, lower alkoxy ortrifluoromethyl and a is an integer from 1 to 6.

12. A compound of claim 11 wherein said compound is N-[2(2-nitro-1-imidazoly1)ethyl]-p-chlorophenoxyacetamide.

References Cited UNITED STATES PATENTS 3,299,090 1/1967 Hoff et a1.260309 3,336,619 8/1957 Craig et a1 260309.2 3,505,349 4/1970 Beaman eta1. 260309 1 8 OTHER REFERENCES Dorn et a1. Chem. Abst. vol. 68,Abstract 12894m (1968), QD1.A51.

Hetzheim et a1. Chem. Ber. vol. 100, pages 3418-21 relied upon (1967)QD1.D4.

Tominaga Chem. Abstr. vol. 68, Abstract 78195r (1968), QD1.A51.

NATALIE TROUSOF, Primary Examiner US. Cl. X.R.

260247.1, 247.2 R, 247.5 R, 250 R, 256.4, 268 H, 293.7, 294.8 R, 295 K;424248, 250, 251, 263, 267, 273

UNITED STATES PATENT OFFICE CERTIFICATE OF COR ECTION Dated February29,- 1972 Patent No.

Inventor(s) Beaman and Tautz It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 17, line 15 in references "3,336,619 81957" should be 2, fifi,121 8-1961 Column 16, line 7 of the formula should be R ((IH )n-1I-C-(CH )a-O Signed and sealed this 1st day of August 1972.

(SEAL) Attest:

EDWARD M.F1JETCHER,JR. ROBERT GOTISCHALK Attesting Officer Commissionerof Patents USCOMM-OC 60376-P69 us GOVLKNMINT PRINYING orncr. I969o-Jes-na FORM po-aoso (10-69)

